The goal of this project is to describe systemic regulators of cell proliferation during cell turnover and tumorigenesis. The ideal cancer therapy aims at eliminating abnormally proliferating cells without disturbing tissue physiology. However, our limited understanding about the mechanisms controlling cell proliferation in the complexity of the whole organism restricts the implementation of biomedical approaches to specifically target abnormal cells. Cell proliferation is influenced by local and systemic signals (e.g.: cell turnover age, injury, nutritional status, etc.). Striking differences exist in the proliferative response of normal and neoplastic cells depending on their location along the anteroposterior (AP) axis. However, the basic biological mechanisms underlying regional differences in the growth of normal and tumor cells are unknown. This project addresses basic mechanisms regulating cell proliferation during adult tissue maintenance and tumorigenesis in the complexity of the whole organism. We capitalize on a unique model system, the planarian flatworm, which exhibits evolutionary conservation of signaling pathways with vertebrates including humans, and has accessible adult stem cells (neoblasts) that can be studied in the complexity of the whole body. The neoblasts are the only dividing cells in this animal and support high rates of cellular turnover and regeneration. Our approach manipulates evolutionarily conserved signaling pathways associated with DNA repair and cancer development to study the origin and location of abnormal cells in the complexity of the whole organism. The proposed approach provides a highly innovative and more simplified model for systematic investigation of cancer development and physiological cell turnover. This project is based on a comprehensive interdisciplinary approach that studies adult stem cells in the complexity of the whole organism considering both local and systemic endogenous signals that modulate their behavior. It is unique in assessing cell regulation during the process of tissue regeneration and cell turnover and in abnormal conditions such as cancer. The strategy is designed to follow specific neoblast populations in vivo and to manipulate endogenous signals that control their behavior. Aim 1 will assess the effect of positional information on the proliferative behavior of stem cells during tissue turnover and tumorigenesis. Cell proliferation, migration and differentiation will be measured in animals with abnormal AP polarity, dysfunctional DNA repair mechanisms and hyperproliferative phenotype. Aim 2 will determine whether regional differences in the proliferation of abnormal cells are mediated through tumor suppressors. Our experiments aim at identifying endogenous signals and cell populations involved in early stages of tumor formation. A major impact of these studies will be the elucidation of basic mechanisms regulating cell proliferation in the complexity of the whole organism to enable the implementation of biomedical approaches to target abnormal cells without disturbing physiological functions.